Alcohol and hepatitis C virus (HCV) infection are recognized as independent causes of chronic liver disease and cirrhosis. Further, significant alcohol ingestion, defined variably as >30 gnvday (women) or >50-60 grnlday (men) has been associated with more severe histological disease, including cirrhosis and hepatocellular carcinoma and an accelerated rate of disease progression in patients with chronic HCV infection. The effect of more limited alcohol intake or non-daily drinking patterns on the progression of HCV disease are not known. In this study, we will establish a prospective cohort of at least 550 HCV-infected patients who drink varying amounts of alcohol at study entry. Total lifetime alcohol intake, patterns of alcohol ingestion, and periods of abstinence will be ascertained using validated questionnaires (Skinner, 1979; Russell, 1991) at study entry and annually for four years. Additional data collected at study entry include demographic, epidemiological and dietary history (including duration of HCV infection, mode of acquisition, use of iron supplements). A comprehensive evaluation of HCV RNA including viral titer in serum, liver and peripheral blood mononuclear cells (PBMCs), and baseline quasispecies complexity, will be obtained. Subjects with an alcohol intake of >30 gm/day (females) or >60 gm/day (males) will be counseled to completely abstain. A subset of 150 subjects drinking <15 gm/day (females) or <30 gm/day (males) of alcohol will be randomized to abstinence or no change in alcohol intake (control group). Annually we will readminister an alcohol questionnaire (12-month quantity/frequency questionnaire, National Alcohol Survey) and perform tests for ferritin, transfenin saturation, and serum aminotransferase activity. HCV viral quasispecies variability (assessed by heteroduplex mobility assay) HCV RNA quantitation and cytokine profiles will be compared in different tissue sources (serum, PBMCs and liver). Liver biopsies will be obtained at baseline and at the end of 4 years follow-up to assess severity and progression of liver disease. This study will determine 1) the quantity and pattern of alcohol intake associated with progression of HCV liver disease; 2) whether abstinence from alcohol among "moderate" or "light" drinkers reduces the rate of HCV disease progression; and 3) the host (including proinflammatory or profibrotic host genes which may be activated in the presence of alcohol) and viral factors (including quasispecies heterogeneity which may be altered by alcohol ingestion) which underlie the enhanced rate of disease progression in HCV-infected patients using alcohol.